Recent Research Developments

Index of Recent Research News
September 3, 2003
    Anticancer Drugs in Individual Mitochondria
    Guohua Xiong, Adrian Anderson, and Edgar Arriaga

    Doxorubicin (Adriamycin) is an anthracycline (Figure A) commonly used to treat several forms of cancer. Despite its effectiveness believed to be the result of stabilization effect on topoisomerase-DNA complexes found in the nucleus of the cell, doxorubicin accumulates in other subcellular regions where it may become cytotoxic. In fact, accumulation of doxorubicin in mitochondria has been linked to cardiomyopathies. Until now, the only analytical techniques to study doxorubicin (and its analogues) have been based on fluorescence microscopy. Although these techniques are effective to confirm localization of doxorubicin in the nucleus, they are not adequate to study doxorubicin localization in mitochondria (Figure B).

    Our group has used capillary electrophoresis with post-column laser-induced dual fluorescence detection to detect accumulation of doxorubicin in individual mitochondria. Using this approach, we simultaneously detect fluorescence emitted by a mitochondrion-selective marker (Mitotracker Green, Figure A) and doxorubicin contained within a given organelle. Figure C displays a dual electrpherogram (fluorescence intensity versus time) where each detected mitochondrion produces a 'spike' in the green detector (535 nm) and each organelle containing doxorubicin produces a 'spike' in the red detector (635 nm).

    When this approach was used to investigate the relative abundance of doxorubicin in mitochondria of both drug sensitive (CCL-119) and resistant (CEM/C2) leukemia cell lines (Figure B), it was found that doxorubicin accumulates similarly in the mitochondria of both cell lines. On the other hand, a surprising finding was that only one third of mitochondria are effectively accumulating doxorubicin. This observation poses several questions relevant to the subcellular distribution of doxorubicin and challenges the dogma that all the mitochondria in a cell are responsible for the same biological function.

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